Hemostasis is a complex process which causes the bleeding process to stop. Hemostasis typically can be achieved by mechanical tamponade, e.g., mechanical agents for blockage of a break, blood cloth formation or artificial wound closure. Wheat & Wolf, 36 Urol. Clin. North Am. 265-75 (2009). For instance, mechanical agents, available as sponges, foams or powders of gelatin, collagen, cellulose or other polysaccharide, achieve hemostasis through mechanical tamponade, by swelling at the site of bleeding and molding to the wound shape. Spotnitz & Burks, 48 Transfusion 1502-16 (2008). When these materials are applied to the wound site, platelet stimulation, aggregation, degranulation and release of clotting factors can also occur. Jenkins et al., 132 J. Am. Med. Assoc. 124-32 (1946).
Blood clot formation can be initiated or achieved enzymatically by the use of thrombin, either alone or in combination with mechanical agents (e.g., bovine collagen sponges or porcine gelatin matrix) or fibrin sealants. Spotnitz & Burks, 2008. Thrombin acts by activating platelets at the site of injury and by cleaving fibrinogen to fibrin. Fibrin, in turn, crosslinks into an insoluble network where platelets adhere and form the homeostatic plug. When thrombin and mechanical agents are used in combination, they can act synergistically to stop blood loss. Gill et al., 65 Urology 463-66 (2005). For example, fibrin sealants, which are formulated as mixtures of thrombin and fibrinogen, can recapitulate the last step of the coagulation cascade and exogenously supply the material needed for the formation of the blood cloth. Lowe et al., 48 J. Cardiovasc. Surg. 323-31 (2007).
Hemostasis can also be attained by using reagents that self-crosslink while simultaneously covalently binding the adjacent tissues to physically close the wound site. For example, cyanoacrylate-based adhesives can rapidly polymerize in situ in the presence of endogenous hydroxyl groups through an exothermic reaction. Wheat & Wolf, 2009; Gill et al., 2005; Lowe et al., 2007; Marcovich et al., 57 Urology 806-10 (2001). Another commercially available crosslinking sealant is bovine albumin and glutaraldehyde-based, where glutaraldehyde acts by linking amine groups of albumin to extracellular matrix proteins found at the wound site. Furst & Banerjee, 79 Ann. Thorac. Surg. 1522-29 (2005). Nevertheless, the presence of glutaraldehyde raises toxicity issues. Furst & Banerjee, 2005. Chemical crosslinking polyethylene glycol (PEG)-based sealants have also been used as hemostatic reagents. Preul et al., 107 J. Neurosurg. 642-50 (2007); Torchiana, 18 J. Cardiac. Surg. 504-06 (2003); Wallace et al., 58 J. Biomed. Mater. Res. 545-55 (2001). However, commercial available PEG-based sealants, such as COSEAL® possess certain drawbacks, including limited applicability at pressure sensitive areas.
Although a series of hemostatic agents and tissue adhesives/sealants have been FDA approved and are currently used in the medical practice, control of bleeding in the operating room still presents issue. The currently commercially available formulations still need improvement, for example, for longer degradation time, better adhesive properties, or decreased swelling for applications on certain tissues, such as areas sensitive to nerve compression. Therefore, there is still a need in the art to improve the overall material properties for tissue sealant/adhesive materials.